Pharmacokinetic–pharmacodynamic relationship of NRTIs and its connection to viral escape: An example based on zidovudine

Kleist, Max von; Huisinga, Wilhelm

doi:10.1016/j.ejps.2008.12.010

Cited by 19 publications

(15 citation statements)

References 74 publications

(88 reference statements)

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“…We assumed that the effect of a drug on the targeted process is specified by some parameter , i.e.,assuming some underlying averaged drug concentration , see [39], some fifty percent inhibitory concentration , and some drug specific Hill coefficient , see [14]. For the purpose of the study, this rough approximation is sufficient, however, it is possible to also use time-varying drug concentration resulting from some pharmacokinetic model, or to use more mechanistic effects models [40],[41].…”

Section: Resultsmentioning

confidence: 99%

Drug-Class Specific Impact of Antivirals on the Reproductive Capacity of HIV

2010

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Predictive markers linking drug efficacy to clinical outcome are a key component in the drug discovery and development process. In HIV infection, two different measures, viral load decay and phenotypic assays, are used to assess drug efficacy in vivo and in vitro. For the newly introduced class of integrase inhibitors, a huge discrepancy between these two measures of efficacy was observed. Hence, a thorough understanding of the relation between these two measures of drug efficacy is imperative for guiding future drug discovery and development activities in HIV. In this article, we developed a novel viral dynamics model, which allows for a mechanistic integration of the mode of action of all approved drugs and drugs in late clinical trials. Subsequently, we established a link between in vivo and in vitro measures of drug efficacy, and extract important determinants of drug efficacy in vivo. The analysis is based on a new quantity—the reproductive capacity—that represents in mathematical terms the in vivo analog of the read-out of a phenotypic assay. Our results suggest a drug-class specific impact of antivirals on the total amount of viral replication. Moreover, we showed that the (drug-)target half life, dominated by immune-system related clearance processes, is a key characteristic that affects both the emergence of resistance as well as the in vitro–in vivo correlation of efficacy measures in HIV treatment. We found that protease- and maturation inhibitors, due to their target half-life, decrease the total amount of viral replication and the emergence of resistance most efficiently.

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Section: Resultsmentioning

confidence: 99%

Drug-Class Specific Impact of Antivirals on the Reproductive Capacity of HIV

2010

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“…(iii) Thirdly, and most importantly, the values based on enzymatic activity (as computed in this work) refer to intracellular concentrations of AZT-triphosphate, while the fold change derived by cell-based assays refers to the concentrations of extracellular pro-drug (AZT) added to the medium surrounding the cells. This has important consequences: AZT phosphorylation is known to be non-linear and might be saturated at the bottlenecking step of thymidilate kinase [53], [54]. We have shown previously that the in vivo maximally achievable AZT-TP concentration is close to the clinically achieved AZT-TP concentration in peripheral blood mononuclear cells (PBMCs), when 300 mg AZT is given twice daily, see [53].…”

Section: Discussionmentioning

confidence: 99%

“…This has important consequences: AZT phosphorylation is known to be non-linear and might be saturated at the bottlenecking step of thymidilate kinase [53], [54]. We have shown previously that the in vivo maximally achievable AZT-TP concentration is close to the clinically achieved AZT-TP concentration in peripheral blood mononuclear cells (PBMCs), when 300 mg AZT is given twice daily, see [53]. In order to disproportionately increase the value several hundred-fold, as observed with some mutants e.g.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Polymerase Inhibition by Nucleoside Analogs: Cellular- and Kinetic Parameters of Efficacy, Susceptibility and Resistance Selection

et al. 2012

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Nucleoside analogs (NAs) are used to treat numerous viral infections and cancer. They compete with endogenous nucleotides (dNTP/NTP) for incorporation into nascent DNA/RNA and inhibit replication by preventing subsequent primer extension. To date, an integrated mathematical model that could allow the analysis of their mechanism of action, of the various resistance mechanisms, and their effect on viral fitness is still lacking. We present the first mechanistic mathematical model of polymerase inhibition by NAs that takes into account the reversibility of polymerase inhibition. Analytical solutions for the model point out the cellular- and kinetic aspects of inhibition. Our model correctly predicts for HIV-1 that resistance against nucleoside analog reverse transcriptase inhibitors (NRTIs) can be conferred by decreasing their incorporation rate, increasing their excision rate, or decreasing their affinity for the polymerase enzyme. For all analyzed NRTIs and their combinations, model-predicted macroscopic parameters (efficacy, fitness and toxicity) were consistent with observations. NRTI efficacy was found to greatly vary between distinct target cells. Surprisingly, target cells with low dNTP/NTP levels may not confer hyper-susceptibility to inhibition, whereas cells with high dNTP/NTP contents are likely to confer natural resistance. Our model also allows quantification of the selective advantage of mutations by integrating their effects on viral fitness and drug susceptibility. For zidovudine triphosphate (AZT-TP), we predict that this selective advantage, as well as the minimal concentration required to select thymidine-associated mutations (TAMs) are highly cell-dependent. The developed model allows studying various resistance mechanisms, inherent fitness effects, selection forces and epistasis based on microscopic kinetic data. It can readily be embedded in extended models of the complete HIV-1 reverse transcription process, or analogous processes in other viruses and help to guide drug development and improve our understanding of the mechanisms of resistance development during treatment.

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“…The analog:dNTP molar ratios are associated with antiviral efficacies [19, 23]. However, as NAs, TFV and FTC also have the potential to disturb the dNTP pool, which consists of dATP, dCTP, deoxyguanosine triphosphate (dGTP), and thymidine triphosphate (TTP), given the interactions with the same enzymes in deoxypurine/deoxypyrimidine anabolic and metabolic pathways [26–29].…”

Section: Introductionmentioning

confidence: 99%

Model Linking Plasma and Intracellular Tenofovir/Emtricitabine with Deoxynucleoside Triphosphates

et al. 2016

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The coformulation of the nucleos(t)ide analogs (NA) tenofovir (TFV) disoproxil fumarate (TDF) and emtricitabine (FTC) is approved for HIV-infection treatment and prevention. Plasma TFV and FTC undergo complicated hybrid processes to form, accumulate, and retain as their active intracellular anabolites: TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP). Such complexities manifest in nonlinear intracellular pharmacokinetics (PK). In target cells, TFV-DP/FTC-TP compete with endogenous deoxynucleoside triphosphates (dNTP) at the active site of HIV reverse transcriptase, underscoring the importance of analog:dNTP ratios for antiviral efficacy. However, NA such as TFV and FTC have the potential to disturb the dNTP pool, which could augment or reduce their efficacies. We conducted a pharmacokinetics-pharmacodynamics (PKPD) study among forty subjects receiving daily TDF/FTC (300 mg/200 mg) from the first-dose to pharmacological intracellular steady-state (30 days). TFV/FTC in plasma, TFV-DP/FTC-TP and dNTPs in peripheral blood mononuclear cells (PBMC) were quantified using validated LC/MS/MS methodologies. Concentration-time data were analyzed using nonlinear mixed effects modeling (NONMEM). Formations and the accumulation of intracellular TFV-DP/FTC-TP was driven by plasma TFV/FTC, which was described by a hybrid of first-order formation and saturation. An indirect response link model described the interplay between TFV-DP/FTC-TP and the dNTP pool change. The EC50 (interindividual variability, (%CV)) of TFV-DP and FTC-TP on the inhibition of deoxyadenosine triphosphate (dATP) and deoxycytidine triphosphate (dCTP) production were 1020 fmol/106 cells (130%) and 44.4 pmol/106 cells (82.5%), resulting in (90% prediction interval) 11% (0.45%, 53%) and 14% (2.6%, 35%) reductions. Model simulations of analog:dNTP molar ratios using IPERGAY dosing suggested that FTC significantly contributes to the protective effect of preexposure prophylaxis (PrEP). Simulation-based intracellular operational multiple dosing half-lives of TFV-DP and FTC-TP were 6.7 days and 33 hours. This model described the formation of intracellular TFV-DP/FTC-TP and the interaction with dNTPs, and can be used to simulate analog:dNTP time course for various dosing strategies.

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Pharmacokinetic–pharmacodynamic relationship of NRTIs and its connection to viral escape: An example based on zidovudine

Cited by 19 publications

References 74 publications

Drug-Class Specific Impact of Antivirals on the Reproductive Capacity of HIV

Drug-Class Specific Impact of Antivirals on the Reproductive Capacity of HIV

HIV-1 Polymerase Inhibition by Nucleoside Analogs: Cellular- and Kinetic Parameters of Efficacy, Susceptibility and Resistance Selection

Model Linking Plasma and Intracellular Tenofovir/Emtricitabine with Deoxynucleoside Triphosphates

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